One of the key characteristics of cancer cells is the increased rate of proliferation. Often the rate of proliferation exceeds de novo vascular formation. As a result, tumor cells may out-grow the available blood supply, and shortage of blood leads to hypoxia (low oxygen level). To overcome hypoxia, tumor cells tend to rely on glycolysis for ATP production (17). High glycolysis rate is characteristic of solid tumors, and is associated with an over-expression of glucose transporters (GLUTs) and glycolytic enzymes.
Thus, a high rate of glucose uptake and increased glucose metabolism are involved in maintaining proliferation of tumor cells (18). This phenomenon is commonly known as Warburg effect (19). It was observed that the initial high level of anaerobic glycolysis resulted in the accumulation of lactate (20). The enzyme (lactate dehydrogenase) responsible for the conversion of pyruvate to lactate was also observed to be elevated in the cancer cells (20). However, lactate dehydrogenase also helps in the survival of the cells under hypoxic conditions by anaerobic glycolysis (20). Increased glycolytic enzyme activities have been reported in cancerous cells (21, 22), and have been observed with the progression of cancer from primary breast tumor to the metastatic stage (23, 24).
Transport of glucose across the membrane of cells is facilitated by proteins called glucose transporters (GLUTs). 13 GLUTs have been identified to date, and have been categorized into three classes. Class I includes GLUT1 to GLUT4, class II includes GLUT5, GLUT7, GLUT9 and GLUT11, and class III includes GLUT6, GLUT5, GLUT10, GLUT12 and GLUT13. The different transporters have different kinetics and affinities towards glucose and other hexoses. The expression level of the different GLUTS in various tissues varies depending on the metabolic consumption of glucose by the particular tissue type. GLUT1 is a ubiquitously expressed GLUT and GLUT1 and GLUT3 expression levels have been found to be much higher in cancerous cells than in normal cells (1). This overexpression has been observed in a wide variety of different cancer cell types (2-14). Extensive studies with breast cancer patients indicated increased GLUT1 activity among the patients (15, 16).
Metabolic targeted cancer therapy is a relatively new field in cancer therapeutic research and is designed to take advantage of the inherent hyper-metabolic characteristics of cancer cells.
Certain previous studies focused on developing therapeutic drugs based on the metabolism of cancer cells. Glufosfamide is a small molecule generated by the conjugation of ifosfamide and glucose. This compound enters the cancer cells through the GLUT proteins. It breaks down in the cell, leading to the release of the toxin (ifosfamide) inside the cell (25-28).
Other groups have used different glucose analogs in an attempt to reduce the glucose metabolism in cancer cells (29, 30). Of the various compounds, 2-deoxyglucose (2-DG) has been shown to be a promising analog. 2-DG is an orally administered glucose analog that inhibits the glycolysis pathway of ATP production in cancer cells. 2-DG accumulates in the cancer cells because the phosphorylated 2-DG cannot be processed by glycolytic enzymes (31, 32). 2-DG can elicit 50% apoptotic cells at a concentration of 4 mM in the SkBr3 (human breast cancer) cell line (33). In vivo animal studies with 2-DG have shown that the growth of the tumor was inhibited with supplemental 2-DG (31, 34).
Noguchi et al. have used anti-sense against GLUT-1 to suppress tumor growth in MKN45 (gastric cancer) cell line. Comparison of tumor development in nude mice demonstrated that the cells expressing anti-sense GLUT-1 develop tumor much more slowly than the wild-type cells (35).
In a more recent study, monoclonal antibody against GLUT-1 was shown to induce growth arrest and apoptosis in breast cancer and lung cancer cell lines. 50% and 75% reductions in cell growth were found in lung cancer and breast cancer cell lines, respectively (36).